Pyrrolo isoindoles and process for preparing same



United States Patent 3,056,800 PYRROLO ISOINDOLES AND PROCESS FORPREPARING SAME Max Francois Antoine Viscontini, Zurich, and Kurt Adanlr,Muttenz, Basel-Land, Switzerland, assignors to Geigy ChemicalCorporation, Ardsley, N.Y., a corporation of Delaware N0 Drawing. FiledOct. 28, 1960, Ser. No. 65,569 Claims priority, application SwitzerlandOct. 31, 1958 15 Claims. (Cl. 260325) The present invention concerns newN-heterocyclic compounds which can be used in particular aspharmaceuticals and intermediate products in the production ofpharmaceuticals, as well as processes for the production of these newcompounds.

An object of this invention is to provide compounds of the generalformulae N 3 oo 00 on I and -O=C-ON N 3 O 00 on wherein:

X represents a bivalent radical CO-O or -CO--,

R represents hydrogen, lower alkyl, cyclohexyl, phenyl, chlorophenyl,lower alkylphenyl, lower alkoxyphenyl, methylenedioxyphenyl, benzyl,chlorobenzyl, nitrobenzyl, lower alkylbenzyl, lower alkoxybenzyl ormethylenedioxybenzyl, and

R represents lower alkyl, lower chloroalkyl, allyl, cyclohexyl, phenyl,benzyl or benzyloxy-lower alkyl and a process for preparing same.

Compounds of the above general formulae may be present to some extent inthe tautomeric enol forms corresponding to the general formulae In caseswhere R is a phenyl radical or a chlorophenyl,

3,056,806 Patented Oct. 2, 1962 a lower alkylphenyl, a loweralkoxyphenyl or a methylenedioxyphenyl radical, the enol form may evenprevail. However, in order to simplify the following description, allcompounds are referred to therein as having the constitution of dioxocompounds of general Formula I or II.

These compounds of the general Formulae I and II are valuableintermediate products for the production of pharmaceuticals.

A further object of this invention is to provide compounds of thegeneral formulae N 0 CO/ \CIH/ III and

oH0HoN N o 00 on and the tautomeric forms --TH--o-X-R= N o oo (IJH onand (|3HGGN N \CO/ \CEH/ IVa wherein:

X represents a bivalent radical -C0O or CO,

R represents hydrogen, lower alkyl, cyclohexyl, phenyl, chlorophenyl,lower alkylphenyl, lower alkoxyphenyl, methylenedioxyphenyl, benzyl,chlorobenzyl, nitrobenzyl, lower alkylbenzyl, lower alkoxybenzyl ormethylenedioxybenzyl, and

R represents lower alkyl, lower chloroalkyl, allyl, cyclohexyl, phenyl,benzyl or benzyloXy-lower alkyl.

This second group of compounds according to the invention has valuablepharmacological properties. In particular such compounds haveanticonvulsive and anaesthesia-potentiating activity and can be used,among other purposes, as psychosedatives on oral administration. Inaddition, they can also be used as intermediate products for theproduction of other pharmacologically active substances.

In these compounds, lower alkyl radicals R are, e.g.: the methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, n-amyl, isoamyl,n-hexyl or 1,3-dimethylbutyl radical. Examples of substituted phenyl andbenzyl radicals R according to the above definition are: o-tolyl,mt'olyl, p-tolyl, p-ethylphenyl, p-isopropylphenyl, p-tert. butylphenyl,3,4-dimethylphenyl, o-methoxyphenyl, methoxyphenyl, p-methoxyphenyl,p-ethoxyp-henyl, p-isopropoxyphenyl, 3,4-dimethoxyphenyl,o-chlorophenyl, mchlorophenyl, p-chlorophenyl,3,4-dimethylenedioxyphenyl, benzyl, o-methylbenzyl, p-isopropylbenzyl,3,4- dimethylbenzyl, p-methoxybenzyl, p-ethoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, p-chlorobenzyl,3,4-methylenedioxybenzyl, and p-nitrobenzyl radicals.

Lower alkyl and lower chloroalkyl radicals R are, e.g.: the methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, n-amyl,isoarnyl, n-hexyl, fl-chloroethyl and -y-chloropropyl radicals.

Benzyloxy-lower alkyl radicals R are especially 3- benzyloxyethyl and'y-benzyloxypropyl radicals.

Of he new compounds of the general Formula III and Illa those arepreferred wherein the symbols XR together represent lower carbalkoxygroup, a lower chlorocarbalkoxy group or a lower alkanoyl group. Asradicals R the phenyl radical and lower alkyl radicals are of particularvalue.

Compounds of the general Formulae I and II are produced by heatingcompounds of the general formula wherein R represents a radicalcorresponding to the definition for R in particular a low molecularalkyl radical, eg the methyl radical or ethyl radical and X, R and Rhave the meanings given above, in a pyridine base until no more carbondioxide is developed, i.e. until about an equimolecular amount has beenliberated. Advantageously, starting materials of the general Formula Vor VI are boiled under reflux in pyridine, but they can also be heated,for example, in pyridine, a picoline, lutidine, collidine or a mixtureof such methyl pyridines at temperatures between about 100 C. and theboiling temperature of the medium chosen. Starting materials of thegeneral Formula V are, depending on the meaning of X, on the one hand(a-phthalimido-acyl)-malonic acid diesters and on the other'y-phthalimido-fi-keto-u-acyl carboxylic acid esters.

Compounds of the general Formula I with the exception of those in whichR is hydrogen are obtained by a second process ifq-phthalimido-fl-keto-a-acyl car boxylic acid esters of'y-phthalimido-a-acyl-,B-diketones of the general formula wherein:

R represents a radical corresponding to the definition given above for RR represents a lower alkyl radical, a cyclohexyl radical, achlorophenyl, lower alkylphenyl, lower alkoxyphenyl,methylenedioxyphenyl, benzyl, chlorobenzyl, nitro- -benzyl, loweralkylbenzyl, lower alkoxybenzyl and methylenedioxybenzyl radical,

VIII

wherein X, R and R have the meanings given above, Which formula isembraced by general Formula I.

Compounds of the general Formula I are obtained by a third process ifstarting materials of the general formula wherein X, R R R and K; havethe meanings given above, are heated at temperatures between 80 and 200C. in sodium acetate which can be either crystalline or anhydrous. Inthis reaction, the acyl radical COR if present and if not, a carboxylicacid ester group is split off, CO being developed. The startingmaterials of the general Formula X are identical with those compounds ofthe general Formula V in which X is COO and the starting materials ofthe general Formula IX, provided that R therein is not hydrogen, areidentical with those of general Formula VII.

These three processes difl'er not only by the reactants necessary forthe elimination of a radical and ring closure and the starting materialsnecessary for each. Far more important is the fact that although in eachcase an acyl radical and a carboxylic acid ester group is present, inthe first process it is the carboxylic acid ester group and in thesecond and third processes it is the acyl group which is split off.Thus, for the production of end products having a l-acyl group (X CO),in the first process, y-phthalamido-fi-keto-ot-acyl carboxylic acidesters can be used whilst for the production of the same compounds bythe second or third process the generally more difficultly produced'y-phthalimido-a-acyl-B-diketones are necessary.

The starting materials of the general Formula V are obtained, forexample, by condensing an a-phthalimidocarboxylic acid halide of thegeneral formula I R1 XI wherein Y is chlorine or bromine and R has themeaning given above, by means of a metal of the first or second group orby means of a derivative of such a metal,

with a malonic acid ester or a B-keto-carboxylic acid ester of thegeneral formula CHZ-X R2 XII wherein X, R and R have the meanings givenabove.

In this condensation, examples of condensing agents are: lithium,sodium, potassium or magnesium or derivatives of these metals such as,e.g. alcoholates, the amides or hydrides in a polar or non-polar organicsolvent or in a mixture of such solvents. The magnesium alcoholates suchas, e.g. magnesium ethylate, are particularly suitable condensingagents.

In an analogous manner, halides of general Formula XI can be condensedwith cyanoacetic acid esters of the general formula COOR3 our-N XIII inorder to yield starting compounds of general Formula VI, or with malonicacid esters of the general formula C OO-R3 whereby starting compounds ofGeneral Formula X are obtained.

Starting compounds of general Formula VII are also obtained in ananalogous manner by condensing an aphthalimido-carboxylic acid halide ofthe general formula wherein R and Y have the meanings given above, witha B-keto-carboxylic acid ester or with a fi-diketone of the generalformula wherein X, R and R have the meanings given above.

As will be seen from the definitions of the symbols R R R R R and X, ashas been said with regard to 4 the starting compounds as defined ingeneral Formulae V-XI, also the general Formulae XI and XVI embrace tosome extent the same compounds; in particular all halides of the generalFormula XV are embraced by general Formula XI.

On the one hand, starting compounds of the general Formula V are(u-phthalimido-acyl)-malonic acid diesters such as e.g., the dimethylesters, diethyl esters, di-n-propyl esters, di-n-butyl esters, diallylesters, di-fichloroethyl esters, di-v-chloropropyl esters, diphenyl es 0ters, dibenzyl esters and di-B-benzyloxyethyl esters of 6[a-phthalimido-fi- (p-nitrophenyl) -propionyl] -.malonic acid.

These compounds are also suitable as starting materials of the generalFormula X for the third production process mentioned.

On the other hand, general Formula V also embraces'y-phthalimido-B-keto-a-acyl carboxylic acid esters such as, e.g. themethyl esters and ethyl esters of 'y-phthalimido-fl-oxo-a-acetyl-butyricacid,

'y'phthalimido-fi-oXo-a-acetyl-valeric acid,

' -phthalimido-B-oxo-a-propionyl-valeric acid,

'y-phthalimido-fl-oxo-oz-butyryl-valeric acid,

'y-phthalimido-B-oxo-a-acetyl-hexanoic acid,

'y-phthalimido-B-oxo-ot-acetyl-heptanoic acid,

'y-phthalimido-6-methyl-5-oxo-wacetyl-hexanoic acid,

'y-phthalimido-fl-oxo-a-acetyl-octanoic acid,

* -phthalimido-'y-cyclohexyl-,B-oxo-a-acetyl-butyric acid,

' -phthalimido-- -phenyl-B-0xo-abutyryl-butyric acid,

-phthalimido- -phenyhfl-oxo-u-isobutyryl-butyric acid,

'y-phthalimido-'y-phenyl-B-oXo-a-benzoyl-butyric acid,

' -phthalimidoy-phenyl-f3-oxo-ot-phenylacetyl-butyric acid,

-phthalimido-y- (p-methylphenyl) -fl-OXO-CL-3.Ctylbutyric acid,

'y-phthalimido-v- (p-isopropylphenyl) /3-OXOoL-:B.C61ZY1- butyric acid,

'y-phthalimido-y- (p-chlorophenyl) -B-oXo-u-acetylbutyric acid,

'yphthalimid0-'yp-methoxyphenyl) /3-oXo-a-acetylbutyric acid,

' -phthalimido--phenyl-fl-oxo-a-acetyl-valeric acid,

y-phthalimido-6- (p-nitrophenyl) -p-oxo-a-acetyl-valeric acid,

' -phthalimido-fi- (p-isopropylphenyl) -fl-oxo-a-acetylvaleric acid,

'y-phthalimid0-B- 3,4-dimethoxyphenyl) -,8-oxo-a-acetyl- Valerie acidand -phthalimido-6- 3 ,4,5-trimethoxyphenyl -;3-oxo-aacetyl-valericacid.

The above compounds are also suitable as starting compounds of generalFormula IX for the third production process and, with the exception ofthe esters of 7- phthalimido-fi-oxo-a-acetyl-butyric acid, as startingcompounds of general Formula VII for the second production process. As,in these processes, the acyl group is split off, the use of compoundshaving an m-acyl radical other than the acetyl radical is of lessinterest. On the other hand, because of the retention of the carboxylicacid ester group, esters other than the methyl and ethyl esters arevaluable as starting materials for the second and third productionprocesses, for example, the n-propyl esters, isopropyl esters, n-butylesters, isobutyl esters, sec. butyl esters, tert. butyl esters, allylesters, phenyl esters and benzyl esters.

Examples of other starting materials embraced by general Formula IX are3-(a-phthalimido-acetyl)-pentane- 2,4-dione, and4-(a-phthalimido-acetyl)-heptane-3,5 -dione. Examples of startingmaterials embraced by both general Formula VII and IX are3-(a-phthalimido-propionyl)-, 3 (a phthalimido butyryl) 3-a-phthalimido-isovaleryl) 3-(et-phthalimido-ot-phenyl-acetyl)-,3-(a-phthalimido B- phenyl-propionyl and 3- a-phthalimido-w 3,4-methylenedioxy-phenyl) -acetyl] -pentane-2,4-dione,4-(a-phthalimido-a-phenyl-acetyl) -heptane 3,5 dione, 4-

(wphthalimido-a-phenyl-acetyl) 2,6 dimethyl heptane-3,5-dione,3-(a-phthalimido-a-phenyl acetyl) 5'- methyl-hexane-2,4-dione,3-(a-phthalimido a phenylacety1)-l-phenyl-butane-1,3-dione and2-(a-phthalimido-aaphenyl-acetyl) 1 phenyl pentane- 2,4-dione.

Examples of starting compounds of general Formula VI are(a-phthalimido-acetyl)-, (a-phthalimido-propionyl)-,(a-phthalimido-isovaleryl)-, (a-phthalimido a phenylacetyl)-, (aphthalimido ,8 phenyl propionyl) and(wphthalimido-'y-phenyl-butyryl)-cyanoacetic acid ethyl esters as wellas other cyanoacetic acid derivatives corresponding to the examples ofmalonic acid derivatives of general Formula V.

Compounds of the general Formulae III and IV are obtained by treatingcompounds of the general Formulae I and II in an organic medium at atemperature between and 50 C. with an alkali metal borhydride, inparticular with sodium borhydride. Surprisingly, not the reduction ofthe keto group which was principally to be expected, but that of thedouble bond occurs in this reaction.

Pyridine in particular is suitable as reaction medium and also assolvent for the sodium borhydride. Also, tetrahydrofuran or dioxan,possibly in admixture with diethyl ether or another dialkyl ether can beused as reaction medium especially with starting materials having amarked tendency to enolisation and salt formation, i.e. mainly withcompounds in which R is an aromatic radical and -XR is an ester group.In this case, the sodium borhydride, e.g. as solution in aqueousethanol, is added to the previously prepared solution of the startingmaterial.

The following examples further illustrate the production of the newcompounds according to the invention. Parts are given therein as partsby weight and their relationship to parts by volume is as that ofgrammes to cubic centimetres. The temperatures are in degreesCentigrade. With regard to the examples which give no amount of thestarting compound, it should be noted that the ratio of startingcompound to condensing agent, i.e. to the pyridine base or ammonia or tothe sodium acetate, can be quantitatively always the same in theexamples which give the amounts of starting compounds independently ofthe molecular weight of the starting compound. However, when ammonia isused as condensing agent at higher temperatures, a great excess thereofshould not be used in order to avoid side reactions.

All reactions are performed in an atmosphere of nitrogen.

Example 1 3 parts of magnesium are dissolved while excluding moisture inparts of anhydrous ethanol, then 15 parts of acetoacetie acid ethylester dissolved in 50 parts by volume of anhydrous ether are added andfinally, a solution of 30 parts of a-phthalimido-ot-phenyl-acetylchloride in 200 parts by volume of anhydrous benzene are added dropwise.On completion of the reaction, the magnesium complex formed isdecomposed with dilute, cooled sulphuric acid, the organic phase isisolated, washed and dried and concentrated. The'y-phthalimido-'y-phenyl-fioxo-a-acetyl-butyric acid ethyl ester whichremains gradually crystallises. It is obtained on recrystallisation fromethanol in the form of long, colourless prisms which melt at 115 40parts of this product are dissolved in ethanol, parts by volume of an 8%ethanolic ammonia solution are added dropwise and the reaction mixtureis left to stand in the cold for about 15 hours while excluding air.3-phenyl-2,5(3H)-dioxo-5H pyrrolo[2,l a]isoindole-1- carboxylic acidethyl ester separates out in the form of red-brown crystals. It can berecrystallised, for example from ethanol. It melts at 167.

Example 2 Analogously to Example 1, 6 parts of magnesium are dissolvedin 40 parts of anhydrous ethanol, reacted with parts of acetoacetic acidmethyl ester and then reacted with 60 parts ofa-phthalimido-a-phenyl-acetyl chloride in 400 parts by volume ofanhydrous benzene. After working up in the usual way,'yaphthalimido-y-phenyl-d oxo-a-acetyl-butyric acid methyl ester isobtained which crystallises immediately in methanol. The colourlessprisms melt at 162.

23 parts of this compound are dissolved hot in 160 parts by volume ofethanol and 7 parts by volume of concentrated ammonia and 20 parts byvolume of water are added while excluding air. After boiling for 3minutes under reflux, the reaction mixture is cooled. A strongexothermic reaction takes place and red crystals are formed. These arefiltered off under suction and washed with ethanol. On recrystallisingfrom glacial acetic acid, 3- phenyl-2,5(3H)-dioxo-5H pyrrolo[2,1a]isoindole 1- carboxylic acid methyl ester is obtained in the form ofred crystals which melt at 176.

Example 3 1.5 parts of magnesium are dissolved in 10 parts of anhydrousethanol and 25 parts by volume of anhydrous ether while excludingmoisture and then 10 parts of acetoacetic acid tert. butyl esterdissolved in 25 parts by volume of anhydrous ether are slowly added.After 1 hour, a solution of 15 parts of a-phthalimido-a-phenyl acetylchloride in parts by volume of anhydrous benzene is added dropwise whilecooling. On completion of the reaction,'y-phthalimido-y-phenyi-[B-oxo-a-acetyl butyric acid tert. butyl esteris obtained by the method given in Example 1. It is a yellowish oilwhich solidifies in alcohol and ether and, when recrystallised fromethanol, melts at 127.

11') parts of this product are treated as described in Example 2 withconcentrated ammonia. The 3-phenyl- 2,5(3i-l)-dioxo-5H-pyrrolo[2,1-a1isoindole 1 carboxylic acid tert. butylester formed separates in the form of redbrown needles and can berecrystallised for example from ethanol. It melts at 152.

Example 4 With a-phthalimido-w(p-methoxyphenyl)-acetyl chloride,'y-phthalimido-y-(p-methoxyphenyl)-,B-oxo-tx acetylbutyricacid ethylester is obtained as given in Example 1. it can be recrystallised forexample from alcohol and melts at 138.

3-(p-methoxyphenyl) 2,5(3H) dioxo 5H pyrrolo-[2,1-a]isoindole-l-carboxylic acid ethyl ester is obtained therefromwith ammonia analogously to Example 1 or 2. 1t crystallises in violetneedles and melts at 160.

3-(p-ethoxyphenyl)-2,5(3H) dioxo pyrrolo [2,1 a] isoindole-l-carboxylicacid ethyl ester is obtained in an analogous manner starting from'y-phthalimido-y-(p-ethoxyphenyl) -B-oxo-a-acetyl-butyric acid ethylester.

Example 5 3 parts of magnesium are dissolved in 20 parts of alcohol and50 parts by volume of ether while excluding moisture, then 23.6 parts ofacetoacetic acid benzyl ester dissolved in 50 parts by volume of etherare slowly added. After 4 hours, 30 parts of a-phthalimido-a-(methoxyphenyD-acetyl chloride in 200 parts by volume of anhydrousbenzene are added. On completion of the reaction, the product is workedup analogously to Example 1. They-phthalimidoy-(p-methoxyphenyD-fioxo-a-acetyl-butyric acid benzyl esterformed melts at On treating with ammonia analogously to Examples 1 and2, 3 (p methoxyphenyl) 2,5 (3H) dioxo 5H- pyrrolo[2,1 ajisoindole 1carboxylic acid benzyl ester is obtained; M.P.

Example 6 With a phthalimido 0: (p chlorophenyl) acetyl chloride, '7'phthalimido 'y (p chlorophenyl) fioxo a acetyl butyric acid ethyl ester(MP. 101) is obtained analogously to Example 1.

Analogously to Example 1 or 2, this product produces with ammonia 3 (pchlorophenyl) 2,5(3H) dicxo- 5H pyrrolol2,1 a]isoindole 1 carboxylicacid ethyl Example 7 Analogously to Example 2, 'y phthalimido 'y (3,4-methylene dioxyphenyl) B oxo a acetyl butyric acid methyl ester (M.P.156) is obtained from a phthalimido t (3,4 methylenedioxyphenyl) acetylchloride. The ethyl ester melts at 153 and the tert. butyl ester melts.at 136.

3 (3',4' methylenedioxyphenyl) 2,5(31-1) dioxo- 5H pyrrolo [2,1a]isoindole 1 carboxylic acid methyl ester, (M.P. 184185), and the ethylester (M.P. 161-162) and the tert. butyl ester are obtained from thecorresponding esters and ammonia analogously to Example 1 or 2.

Example 8 'y Phthalimido 6 phenyl 5 oxo 0c acetyl Valerie acid ethylester is obtained with u-phthalimido-fi-phenylpropionyl chlorideanalogously to Example 1. Recrystallised from ethanol it melts at 102.

23 parts of this compound are dissolved in 150 parts by volume of 80%ethanol and 6 parts by volume of concentrated ammonia in parts by volumeof water are added at 80 while excluding air. On completion of thereaction, the reaction mixture is cooled and the product whichprecipitates is recrystallised from ethanol. 3 benZyl 2,5(3H) dioxo 5Hpyrrolo[2,1 alisoindole- 1 carboxylic acid ethyl ester is obtained asyellowish prisms which melt at 135.

Example 9 'y Phthalimido B oxo a acetyl valeric acid methyl ester isobtained with a phthalimido propionyl chloride analogously to Example 2.It melts at 102.

6.5 parts thereof are dissolved in 50 parts by volume of 80% ethanol and2 parts by volume of concentrated ammonia are added at 80 whileexcluding air. When the solution has turned a dark red colour (afterabout minutes), it is cooled. After cooling for a considerable time withice, redprisms separate out. Recrystallised from ethanol, 3 methyl2,5(3H) dioxo 5H- pyrrolo[2,1 a]isoindole 1 carboxylic acid methyl esteris obtained in the form of yellow-orange prisms which melt at 145.

Example 10 With 04 phthalimido isovaleryl chloride analogously toExample 1, 'y phthalimido l3 oxo on acetyl 6- methyl heptanoic acidmethyl ester is obtained which without being crystallised is reacteddirect with ammonia analogously to Example 9.

The 3 isopropyl 2,5(3H) dioxo 5H pyrrolo[2,1- a]isoindole 1 carboxylicacid methyl ester obtained in yellow-orange platelets when crystallisedfrom ethanol, melts at 122.

Example 11 'y Phthalirnido 'y (p chlorophenyl) fi oxo aacetyl butyricacid allyl ester is produced analogously to Example 1 with a phthalimidoa -(p chlorophenyl)- acetyl chloride and acetoacetic acid allyl ester.This product is reacted direct with ammonia analogously to Example 2without previously purifying 3 (p chlorophenyl) 2,5(3H) dioxo 5H pyrrolo[2,1 a]isoindole 1 carboxylic acid allyl ester can be recrystallisedfrom ethanol and is obtained in the form of red-brown needles. MP. 170".

Example 12 'y Phthalimid-o 'y -phenyl [3 oxo 0c acetyl butyric acidbenzyl ester is produced as described in Example 5 with at phthalimido0L phenyl acetyl chloride. The colourless crystals obtained melt at 131.

On treatment with ammonia analogously to Example 1 or 2, 3 phenyl2,5(3H) dioxo 5H pyrrolo[2,1- a]isoindole 1 carboxylic acid benzyl esteris obtained.

10 Recrystallised from ethanol it is in the form of red" brown needlesand melts at 158.

Example 13 v Phthalimido 'y (p isopropylphenyl) 5 oxo uacetyl butyricacid ethyl ester is produced as described in the above examples with u(p isopropylphenyD- acetyl chloride and acetoacetic acid ester. It meltsat 108.

On treating with ammonia analogously to Example 1 or 2, 3 (pisopropylphenyl) 2,5(3H) dioxo 5H- pyrrolo[2,1 alisoindole 1 carboxylicacid ethyl ester is obtained, 175.

Starting from y phthalimido 'y (p methylphenyl)- ,8 oxo rx acetylbutyric acid ethyl ester, 3 (p -metl1- ylphenyl) 2,5(3H) dioxo 5H ipyrrolo[2,1 alisoindole l carboxylic acid ethyl ester is obtained andstarting from 7 phthalimido 3,4 dimethylphenyl) B- oxo 0c acetyl butyricacid ethyl ester, 3 (3,4' dimethylphenyl) 2,5(31-1) dioxo 5H pyrrolo[2,1a] isoindole 1 carboxylic acid ethyl ester is obtained in an analogousmanner.

Example 14 A magnesium ethylate solution is prepared While excludingmoisture from 1.5 parts of magnesium and 12 parts by volume of ethanoland 6 parts of acetyl acetone dissolved in 50 parts of volume ofanhydrou ether followed by 12.5 parts of oephthalimido :x-phenyl acetylchloride dissolved in parts by volume of benzene are slowly added to themagnesium solution. On completion of the reaction, the magnesium complexcompound is decomposed by carefully adding dilute, cooled sulphuricacid. The organic phase is then separated, washed with Water, dried andconcentrated.

The 3 (o: phthalimido a phenyl acetyl) pentane 2,4 dione which remainsas crude product is dissolved in ethanol, 12 parts of 8% ethanolicammonia solution are added and the whole is left to stand for about 15hours. The product is worked up analogously to Example 1. The 1 acetyl 3phenyl 5H pyrrolo [2,1 alisoindole 2,5(3l-l) dione obtained.crystallises in yellow prisms and melts at 183.

Example 15 39.3 parts of -phthalimido- -phenyl-p-oxo-a-acetylbutyricacid ethyl ester described in Example 1 are refluxed in 200 parts ofanhydrous pyridine until no more CO is developed. After about 10 hours,the reaction solution is poured onto ice, it is acidified withconcentrated hydrochloric acid and the precipitated red-brown crude1-acetyl-3-phenyl-SH-pyrrolo[2,1-a]-isoindole-2,5- (3H)-dione isisolated. It is recrystallised from ethanol when it is then in the formof yellow platelets which melt at 183. It is identical with the compounddescribed in Example 14.

Example 16 3 parts of magnesium are dissolved in 20 parts of anhydrousethanol while excluding moisture, 16 parts of malonic acid diethyl esterdissolved in 50 parts by volume of anhydrous ether are slowly added andthen a solution of 30 parts of a-phthalimido-a-phenyl acetyl chloride in200 parts by volume of anhydrous benzene is added dropwise. Oncompletion of the reaction, the magnesium complex formed is decomposedwith dilute, cooled sulphuric acid, the organic phase is isolated,washed, dried and concentrated. The remaining(u-phthalimido-a-phenyl-acetyl)- malonic acid diethyl ester is dissolvedin hot alcohol from which it crystallises in the form of colourlessneedles. It melts at l05-106.

4.23 parts of this product in 25 parts by volume of anhydrous pyridineare refluxed for 14 hours. The reaction solution is then poured ontoice, acidified with concentrated hydrochloric acid and the precipitatedred 3 phenyl 2,5 (3H)-dioxo-5H-pyrrolo[2,1-a1isoindole-1- carboxylicacid ethyl ester is isolated. It melts at 167 1 1 and is identical withthe compound described in Example 1.

Example 17 'y Phthalimido 7 phenyl-p-oxo-a-acetyl-butyric acid methylester is produced with 12 parts of acetoacetic acid methyl esteranalogously to Example 16. Recrystallised from methanol it melts at 160.

3.8 parts of this compound in 25 parts by volume of anhydrous pyridineare refluxed for 8 hours. The reaction solution is then poured intoice-cold hydrochloric acid and the precipitated red-brown product isisolated. After recrystallising from ethanol, it melt at 183. Thecompound is identical to that described in Examples 1 and 16.

Example 18 'y Phthalimido 'y phenyl-e-oxo-a-cyano-butyric acid ethylester is produced with 12 parts of cyanoacetic acid ethyl esteranalogously to Example 16. M.P. 148 from ethanol.

5.5 parts of this compound in 50 parts by volume of pyridine arerefluxed for 9 hours. The reaction solution is then poured onto ice andacidified with concentrated hydrochloric acid. The precipitatedl-cyano-3-phenyl- SH-pyrrolo[2,l-a]isoindole-2,5(3H)-dione isrecrystallised from ethanol. It separates in the form of yellowbrownprisms and melts at 198.

3.4 parts of 2-cyano-3-oxo-4-phthalirnido-S-methylcaproic acid ethylester (produced from u-phthalimidoisovaleryl chloride and cyanoaceticacid ethyl ester analogously to Example 16) in 25 parts by volume ofpyridine are refluxed for 20 hours. The reaction solution is then pouredonto ice and the pH is adjusted to about 4 with concentratedhydrochloric acid. After stirring vigorously, the precipitated1-cyano-3-isopropyl-5H-pyrrolo- [2,1-a]isoindole-2,5(3H)-dione isseparated, washed neutral and recrystallised from alchol. It formsyellow prisms which melt at 149151.

Example 19 'y Phthalimido 6 phenyl B-oxo-a-acetyl-valeric acid ethylester is obtained with a-phthalimido-B-phenylpropionyl chlorideanalogously to Example 1. Recrystallised from ethanol it melts at 102.

4.08 parts of this compound in 25 parts by volume of anhydrous pyridineare refluxed until no more CO is developed. The reaction solution isthen poured onto ice and the pH is adjusted to 2 with concentratedhydrochloric acid. The yellow-red sticky mass is isloated, washed withwater and recrystallised from ethanol. l-acetyl-3-benzyl-5H-pyrrolo[2,1-a] isoindole-2,5( 3H)-dione is in the form of yellow platelets. Itmelts at 140.

1 isobutyryl-3-benzyl-5H-pyrrolo[2,l-a]isoindole-2,5- (3H)-dione (M.P.133l35) is obtained in an analogous manner starting from'y-phthalimido-fi-phenybfl-oxo-aisobutyryl-valeric acid ethyl ester.

Example 20 'y-Phthalimido-p-oxo-a-acetyl-valeric acid methyl ester (M.P.102) is obtained with a-phthalimido-propionyl chloride analogously toExample 1.

3.17 parts of this compound in 25 parts by volume of anhydrous pyridineare refluxed until no more CO is developed. The reaction solution isthen poured onto ice, the pH is adjusted to about 2 by stirring withconcentrated hydrochloric acid and the precipitated brown residue isisolated, washed with water and dissolved in hot ethanol. 1 acetyl3-methyl-5H-pyrrolo[2,1-a]isoindole-2,5 (3H)- dione separates in theform of pale yellow needles. It melts at 142.

Example 21 'y-Phthalimido-B-oxo-u-acetyl-butyric acid ethyl ester (M.P.137) is obtained with e-phthalimido-acetyl chloride analogously toExample 1.

3.18 parts of this compound in 25 parts by volume of sym. collidine areheated to 160-180 for about 14 hours. The reaction solution is thenpoured onto ice, the pH is brought to about 2 with concentratedhydrochloric acid, the precipitated brown mass is isolated and rubbedwith ether. 1 acetyl-SH-pyrrolo[2,1-a]isoindole-2,5(3H)-dione separatesin yellow-brown prisms which melt at 217.

Example 22 (a-Phthalimido-[R-phenyl-propionyl)-malonic acid diethylester is obtained with a-phthalimido-B-phenyl-propronyl chlorideanalogously to Example 16 and it is treated with pyridine direct in itscrude oily form analogously to Example 19. The 3-benzyl-2,5(3H)-dioxo-5H-pyrrolo- [2,1-a]isoindole-l-carboxylic acid ethyl esterobtained melts at 135 and is identical with the compound obtainedaccording to Example 8.

In an analogous manner, 3-(p-chlorobenzyl)-2,5(3H)-dioxo-SH-pyrrolo[2,l-a]isoindole-l-carboxylic acid ethyl ester (M.P.l6l162) is obtained from[a-phthalimidofi-(p-chlorophenyl)-propionyl]-malonic acid diethyl ester;3 (p methylbenzyl)2,5(3H) dioxo 5H pyrrolo-[2,l-a]isoindole-1-carboxylic acid ethyl ester is obtained from [aphthalimido 5 (p-methylphenyl)-propionyl]- malonic acid diethyl ester;S-(p-isopropylbenzyl)-2,5- (3H) dioxo 5H pyrrolo[2,1-a]isoindole 1 canboxylic acid ethyl ester is obtained from[a-phthalimrdop-(p-isopropylphenyl)-propionyl]-malonic acid diethylester; (3-phenyl-2,5 (3H) -dioxo-5H-pyrrolo [2, l-a]isomdole-l-carboxylic acid phenyl ester is obtained from(ocphthalimido-a-phenyl-propionyl)-malonic acid diphenyl ester; 3phenyl-2,5(3H)-dioxo-5H-pyrrolo[2,1-a]isoindole-l-carboxylicacid-fi-chloroethyl ester, M.P. l87 189 is obtained from(a-phthalimido-wphenylpropionyl)-malonic acid di-B-chloroethyl ester;3-phenyl- 2,5 (3H)-dioxo-5H-pyrrolo[2,1-a]isoind0le-1 carboxylicacid-'y-chloropropyl ester is obtained from(a-phthalimidoa-phenyl-propionyl)-malonic acid-diy-chloropropyl ester; 3(4' methoxybenzyl)-2,5(3H)-dioxo-5H-pyrrolo[2,1-a]isoindole-1-carboxylic acid ethyl ester is obtained from [aphthalimido ,8 (4 methoxyphenyl) propionyl]- malonic acid diethyl ester,M.P.97-98"; 3-(4-ethoxybenzyl) 2,5(3H) dioxo 5H pyrrolo[2,1a]isoindolel-carboxylic acid ethyl ester is obtained from[a-phthalimido-fl-(4-ethoxyphenyl)-propionyl]-malonic acid diethylester; 2-(3,4-dimeth0xybenzyl)-2,5(3H)-dioxo-5H-pyrrolo[2,l-a]isoindole-l-carboxylic acid ethyl ester, the enol acetateof which melts at 143145 is obtained from [a-phthalimido-fi-(3Adimethoxyphenyl) propionyl]- malonic acid diethyl ester;3-phenyl-2,5(3H)-dioxo-5H- pyrrolo[2,l-a]isoindole l-carboxylicacid-fl-benzyloxyethyl ester, M.P. 108110, is obtained from(a-phthalimido-a-phenylpropionyl)-malonic acid di-B-benzyloxyethylester;3-(3,4'-methylenedioxy)-benzyl-2,5(3H)-dioxo-SH-pyrrolo[2,l-a]isoindole-l-carboxylicacid ethyl ester is obtained from[a-phthalimido-y-(3,4-methylenedioxy-phenyl)-propionyl]-malonic aciddiethyl ester, M.P. 8283; 3 [5 (3,4' methylenedioxy phenyl)-ethyl]-2,5(3H) dioxo 5H pyrrolo[2,l-a]isoindole-lcarboxylic acid ethylester is obtained from [a-phthahimido-y-(3,4-methylenedioxy-phenyl)-butyryl] malonic acid diethyl ester.The starting materials given above can be produced analogously toExample 16.

Example 23 a-Phthalimido-propionyl malonic acid diethyl ester isobtained with a-phthalimido-propionyl chloride analogously to Example 16and is treated direct in an oily form with pyridine.3-methyl-2,5(3H)-dioxo-5H-pyrrolo- [2,l-a]isoindole-l-carboxylic acidethyl ester (M.P. 131) is obtained.

Example 24 -Phthalimido-'y-phenyl-fl-oxo-a-butyryl butyric acid ethylester (M.P. is obtained with butyryl acetic acid ethyl ester analogouslyto Example 1. With pyridine analogously to Example 19 it produces1-butyryl-3-phenyl- 1.3 H-pyrrolo[2,1-a]isoindole-2,5 (3H)-dione whichmelts at 168.

1 isobutyryl 3 phenyl-SH-pyrrolo[2,1-a]isoindole- 2,5(3H)-dione isobtained in an analogous manner starting from -phthalimidoy-phenyl-,B-oxo-u-isobutyryl-butyric acid ethyl ester, M.P. l90-l92.

Example 25 y-lhthalimidoq-phenyl-fi-oxo-a-benzoyl-butyric acid ethylester is obtained with benzoyl .acetic acid ethyl ester analogously toExample 1; it melts at 182. With pyridine analogously to Example 19,1-benzoyl-3-phenyl-5H- pyrrolo[2,1-a]isoindole-2,5(3H)-dione isobtained, M.P. 217.

Example 26 Example 27 [a Phthalimido a (3,4' dimethoxyphenyl)propionylJ-malonic acid diethyl ester is obtained analogously to Example16 from a phthalimido 8 (3,4 dimethoxyphenyl)-propionyl chloride, and istreated direct in the oily form, analogously to Example 19, withpyridine. The crude 3 (3,4 dimethoxybenzyl) 2,5(3H)dioxoiiH-pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester istreated with acetoacetic acid anhydride and sodium acetate whichproduces the enol acetate. After recrystallisation from alcohol, theenol acetate melts at 143145.

3 (p methoxybenzyl) 2,5(3H) dioxo 5Hpyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester is obtained in ananalogous manner from [a-phthalimidofi-(p-methoxyphenyl)-propionyl]-malonic acid diethyl ester, MP. 9798.

Example 28 [a-Phthalimido-fi-(3,4-methylenedioxy phenyl)propionylJ-malonic acid diethyl ester is obtained from the correspondingpropionyl chloride by reacting with malonic acid diethyl esteranalogously to Example 16. It melts at 82-83 (from ethanol).

If this compound is boiled in pyridine until no more CO is liberated,then poured onto ice, acidified with concentrated hydrochloric acid,then 3-(3,4-methylenedioxy-benzyl)2,5(3H)-dioxo-5Hpyrrolo[2,l-a]isoindolel-carboxylic acid ethyl ester is obtained.

Example 29 [a Phthalimido B (p chlorophenyl) propionyl]- malonic aciddiethyl ester is obtained as a crude oil from a phthalimido B (pchlorophenyl) propionyl chloride by means of ethoxy magnesium malonicacid diethyl ester analogously to Example 16. This oil is treated directwith pyridine and 3-(pchlorobenzyl)-2,5(3H)-dioxo-5H-pyrrolo[2,l-a]isoindole-l-carboxylic acid ethyl ester is obtained inthe form of orange-red prisms which melt at 16l162 (from ethanol).

Example 30 5.27 parts of[a-phthalimido-B-(3,4,5-trimethoxyphenyl)-propionyl]-malonic aciddiethyl ester (obtained from a-phthalimido-p- 3 ,4,5-trimethoxyphenyl-propionyl chloride and malonic acid diethyl ester analogously to Exam-.ple 16) in 25 parts by volume of pyridine are refluxed until no more COis liberated. The reaction is complete after about 16 hours. Thereaction solution is poured ltd onto ice and acidified with concentratedhydrochloric acid. The sticky product which precipitates is separatedand purified. It is 3-(3,4,5-trimethoxybenzyl)-2,5 (3H)-dioxo-SH-pyrrolo 2, l-a] isoindolel-carboxylic acid ethyl ester.

Example 31 4.8 parts of [aphthalimido-B-(p-nitrophenyl)-propionylJ-malonic acid diethyl ester in30 parts by volume of anhydrous pyridine are refluxed for 12 hours.After cooling, the reaction solution is poured onto ice while stirringvigorously and the pH is adjusted to 2 with concentrated hydrochloricacid. The crude product which precipitates is separated, washed neutraland, after drying in the air, is recrystallised from alcohol. In thisway a good yield of3-(p-nitrobenZyD-2,5(3H)-di.oxo-5H-pyrrolo[2,1-a]-isoindole-l-carboxylicacid ethyl ester is obtained.

Example 32 'y Phthalimido 'y phenyl B-oxo-a-acetyl-butyric acid ethylester produced according to Example 1, or (0:-phthalirnido-a-phenyl-acetyl)-malonic acid diethyl ester producedaccording to Example 16, is heated for 1 hour at about 150 with doubleto triple the amount of sodium acetate (aqueous or anhydrous). Aftercooling, the reaction mixture is rubbed with water. The 3-phenyl-2,5-(3H)-dioxo-5H-pyrrolo [2,1-a] isoindole 1 carboxylic acid ethyl esterobtained is filtered oil under suction, dried and recrystallised fromethanol of xylene, M.P. 166-167".

Example 33 'y Phthalimido 5 phenyl B oxo a acetylvaleric acid ethylester (see Example 19) is mixed with five times the amount ofcrystalline sodium acetate and the mixture is heated for 1 hour at 150.After cooling, the reaction mixture is rubbed with water, the 3-benzyl-2,5(3H)-dioxo-5H-pyrrolo[2,1-a]isoindole 1 carboxylic acid ethyl esterformed is filtered 0E under suction and recrystallised from ethanol.M.P. (See Examples 9 and 22.)

3 cyclohexyl 2,5(3H)-dioxo-5H-pyrrolo[2,1-a]isoindole-l-carboxylic acidethyl ester (M.P. 124; see Example 26) is obtained in an analogousmanner from (ocphthalimido oz cyclohexyl acetyl) malonic acid diethylester.

Example 34 'y Phthalimido B oxo 0c acetyl butyric acid ethyl ester (seeExample 21) is mixed with five times the amount of crystalline sodiumacetate and the mixture is heated for 1 hour at After cooling, thereaction mixture is rubbed with water, the brown mass which precipitatesis isolated and this crude product is rubbed with ether whereupon 2,53H) -dioxo-5I-I-pyrrolol2, l-a] isoindole-l-carboxylic acid ethyl esteris obtained.

Example 35 2.85 parts of 3 isopropyl-2,5(3H)-dioxo-5H-pyrrolo[2,1-a]isoindole-l-carboxylic acid methyl ester are dissolved in 20parts by volume of anhydrous pyridine. The solution is cooled to 05 and0.425 part of sodium borhydride in 15 parts by volume of pyridine areadded with in about 5 minutes while stirring well and cooling. Thesolution which is at first red, gradually turns yellowish. On completionof the dropwise addition, 50 parts by vol ume of ether are added, thewhole is stirred for half an hour and then a further 50 parts by volumeof ether are added. The reaction product is filtered off under suction,washed with ether and dried in the air. It is the sodium salt of theenol form of 3-is0propyl-2,5(3H)- dioxo 10,1dihydro-5Hpyrrolo[2,1-a]isoindole-1-carboxylic acid methyl ester. Thissalt is dissolved in ice water and 2 N-hydrochloric acid or 2N-sulphuric acid or acetic acid is added until there is an acid reaction(pH 4) whereupon a colourless reaction product pre- 15 cipitates. Thisis filtered off under suction and recrystallised from alcohol. It meltsat l35-137.

In the same way, 3-cyclohexyl-2,5(3H)-dioxo'-10,1- dihydro 5Hpyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester, M.P. 127-l28recrystallised from ethanol, and also 1 -acetyl 3 benzyl10,1-dihydro-5l-I-pyrrolo [2,1-a]isoindole-2,5(3H)-dione are produced.After recrystallisation from glacial acetic acid, the latter melts at206-208.

Example 36 2.99 parts of 3-isopropyl-2,5(3H)-dioXo-5H-pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester are treated with sodiumborhydride analogously to Example 1. The reaction solution isconcentrated in vacuo to a small volume and ice water and dilutehydrochloric acid (pH 4) are added to the residue. The precipitatedreaction product is washed with water, filtered oil under suction and,after decolouration with animal charcoal, recrystallised from ethanol.The colourless crystals which melt at 113-114", are 3-isoprcpyl2,5(3H)-dioxo-10,1-dihydro- SH-pyrrolo-[2,1-a]isoindole-l-carboxylicacid ethyl ester.

Also 3 benzyl 2,5(3H) dioxo-10,1-dihydro-5H-pyrrolo[2,l-a]isoindole-l-carboxylic acid ethyl ester (colourlesscrystals, M.P. 108-109), 3-methyl-2,5(3H)-dioxo 10,1 dihydro 5H-pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester and 2,5(3H)-dioXo-10,1-dihydro- SH-pyrrolo[2,1-a]isoindole-l-carboxylic acidethyl ester are obtained in an analogous manner.

Example 37 6.06 parts of1-acetyl-3-phenyl-5H-pyrrolo[2,1-a]isoindole-2,5(3H)-dione are dissolvedin 40 parts by volume of anhydrous pyridine. 0.85 part of sodiumborhydride in 30 parts by volume of pyridine are added dropwise withinabout 10 minutes while cooling with ice and stirring. The solution whichis at first dark red, gradually becomes dark green and, on completion ofthe dropwise addition, yellow brown. The reaction solution is stirredfor another half hour at 5 and then 300 parts by volume of ether areadded whereupon a pale yellowish product precipitates immediately. Afterstirring for a short time and standing at about the product is filteredoff under suction and washed with ether. The filter residue is thesodium salt of the enol form of l-acetyl-3-phenyl- 10,1 dihydro 5Hpyrrolo [2,1-a]isoindole-2,5(3I-I)- dione. This salt is dissolved in icewater and acetic acid, 2 N-hydrochloric acid or 2 N-sulphuric acid isadded to the solution while stirring well until there is an acidreaction (pH 5), whereupon a colourless reaction product precipitateswhich melts at 155-156 when recrystallised from ethanol.

Also, for example, 1-butyryl-3-phenyl-10,l-dihydro- 5H pyrrolo[2,la]isoindole 2,5(3H) dione M.P. 151-l52 recrystallised from ethanol;1-benzoyl-3-phenyl- SH-pyrrolo[2,1-a]isoindole-2,5(3H) dione, M.P. 171-172 recrystallised from glacial acetic acid; l-isobutyryl- 3 phenyl 10,1dihydro 5H pyrrolo[2,1-a]isoindole- 2,5(3H)-dione, M.P. 179-180recrystallised from ethanol, as well as1-isobutyryl-3-benzyl-10,1-dihydro-5H-pyrrolo[2,l-a]isoindole-2,5(3H)-dione, M.P. 189-190 recrystallised fromglacial acetic acid or ethanol are obtained analogously to the aboveexample.

Example 38 5.72 parts of 1 cyano 3 phenyl 5H pyrrolo[2,1- a]isoindole-2,5(3H)-dione are dissolved in 40 parts by volume of pyridineand a solution of 0.85 part of sodium borhydride in 20 parts by volumeof pyridine is added while cooling with ice and stirring. On completionof the dropwise addition, the reaction mixture is stirred for anotherhalf hour. Then 250 parts by volume of ether are added and the whole isstirred for another hour at 0-5. The precipitated reaction product isfiltered oft" under suction, washed with ether, dissolved in ice waterand 2 N-hydrochloric acid is added until the reaction is slightly 16acid (pH 5-6). The precipitated crystalline reaction product is 1 cyano3 phenyl 10,1-dihydro-5H-pyrrolo[2,1-a]isoindole-2,5(3H)-dione. It isfiltered ofi under suction and recrystallised twice from ligroinwhereupon it melts at 106-108".

Example 39 0.85 part of sodium borhydride, dissolved in 35 parts byvolume of pyridine, are slowly added dropwise While stirring and coolingwith ice to a solution of 6.66 parts of 3-phenyl-2,5(3H)-dioxo-5H-pyrrolo [2,1-a]isoindole-1- carboxylic acid ethyl ester in40 parts by volume of pyridine. On completion of the dropwise addition,the reaction mixture is stirred for another 20 minutes under icecooling, then 150 parts by volume of ether are added, stirring iscontinued for another 15 minutes and then the precipitated pale greencrystal powder is filtered oil? under suction. This is suspended inwater, the suspension is acidified with hydrochloric acid (pH 4) and the3 phenyl 2,5(3H) dioxo 10,1 dihydro 5H pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester which is liberated isrecrystallised from ethanol and washed with ether/petroleum ether. Thecolourless platelets so obtained melt at 135-137".

Example 40 7.35 parts of 3-(p-chlorophenyl)-2,5(3H)-dioXo-5H-pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester are dissolvedwhi'le stirring well in 50 parts by volume of tetrahydrofuran. The redsolution is cooled to O-5" whereupon a brown suspension is obtained. 085part of sodium borhydride in 20 parts by volume of about ethanol areadded dropwise within about 10 minutes to the suspension while stirringWell whereupon a colourless product gradually precipitates. Oncompletion of the dropwise addition, the reaction mixture is stirred forone and a half hours at 0 and then 30 parts by volume of ether areadded. The reaction product is then filtered off under suction and thefine crystalline filter cake is dried, if desired in vacuo. It is thesodium salt of the enol form of3-(p-chlorophenyl)-2,5(3H)-dioXo-10,1-dihydro-SH-pyrrolo[2,1-a]isoindole-l-carboxylicacid ethyl ester.

This salt is suspended in ice water and 1 N-sulphuric acid or 2N-hydrochloric acid or acetic acid is carefully added until the reactionis acid (pH 4). The colourless reaction product is filtered off undersuction and recrystallised twice from ethanol whereupon it melts at153-155".

Also for example,3-phenyl2,5(3H)-di0Xo-10,1-dihydro-SH-pyrrolo[2,1-a]isoindole-l-carboxylicacid methyl ester, M.P. 174-176 from ethanol; 3-phenyl-2,5(3H)- dioxo10,1 dihydro 5H pyrrolo[2,1 a]isoindole l-carboxylic acid-fi-chloroethylester, M.P. 148149 from ethanol; 3-phenyl-2,5 (3H)-dioxo-10,1-dihydro-5II- pyrrolo[2,1-a]isoindole-l-carboxylicacid-'y-chloropropyl ester; 3 p methoxy 2,5(3H) dioxo 10,1 dihydroSH-pyrrolo[2,1-a]isoindole-l-carboxylic acid methyl ester; 3 phenyl2,5(3H) dioxo 10,1 dihydro 5H pyrrolo[2,1 a]isoindole 1 carboxylic acid,B benzyl oxy ethyl ester;3-p-methylphenyl-2,5(3H)-dioxo-10,1-dihydro-SH-pyrro'lo[2,1-a]isoindole-l-carboxylic acid ethyl ester;3-(p-isopropylphenyl)-2,5 (3H) ,dioxo-10,1-dihydro-SH-pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester; 3 (3,4dimethylphenyl) 2,5(3H) dioxo 10,1 dihydro-SH-pyrrolo[2,l-a]isoindole-l-carboxylic acid ethyl ester; 3 phenyl2,5(3H) dioxo 10,1 dihydro 5H pyrrolo[2,1-a]isoindole-l-carboxylic acidcyclohexyl ester, M.P. 163164 from ethanol; 3-phenyl-2,5(3H)-dioxo- 10,1dihydro 5H pyrrolo[2,l a]isoindole 1 car boxylic acid benzyl ester, M.P.133-135 from ethanol; 3 (p methoxyphenyl) 2,5(3H) dioxo 10,1 dihydro-SH-pyrrolo [2,1-a] isoindole-l-carboxylic acid ethyl ester, M.P.-112 from ethanol; S-p-ethoxyphenyl- 2,5(3H) dioxo 10,1 dihydro 5Hpyrrolo[2,1 a]isoindole-l-carboxylic acid ethyl ester;3,(3,4'-methylenedioxyphenyl) 2,5 (3H) dioxo 10,1 dihydro Hpyrrolo[2,l-a]isoindole-l-carboxylic acid methyl ester, M.P. 168170 fromethanol are obtained analogously to Example 40, and3-(p-chlorobenzyl)-2,5(3H)-dioxo-10,1- dihydro 5H pyrrolo[2,1a]isoindole 1 carboxylic acid ethyl ester;S-(p-nitrobenzyl)-2,5(3H)-dioxo-10,ldihydro 5H pyrrolo[2,l a]isoindolle1 carboxylic acid ethyl ester; 3-(p-methylbenzyl)-2,5(3H)-dioxo-10,1-dihydro 5H pyrrolo[2,l a]isoindole 1 carboxylic acid ethyl ester;3-(3,4-dimethylbenzyl)2-,5(3H)-dioxo- 10,1 dihydro 5H pyrrolo[2,1a]isoindole 1 car boxylic acid ethyl ester;3-(p-isopropylbenzyl)-2,5(3H)- dioxo 10,1 dihydro 5H pyrrolo[2,1a]isoindole l-carboxylic acid ethyl ester; 3-(p-methoxybenzy1)- 2,5(3H)dioxo 10,1 dihydro 5H pyrrolo[2,l a]isoindole-l-carboxylic acid ethylester; 3-(p-ethoxybenyl) 2,5(3H) dioxo 10,1 dihydro 5H pyrrolo[2,1-a]isoindole-l-carboxylic acid ethyl ester; 3-(3',4'-dimethoxybenzyl) 2,5 (3H) dioxo 10,1 dihydroSH-pyrollo[2,l-a]isoindole-l-carboxylic acid ethyl ester; 3 (3',4,5trimethoxybenyl) 2,5(3H) dioxo 10,1 dihydro 5H pyrrolo[2,1 a]isoindole 1carboxylic acid ethyl ester; 3-(3,4-methylenedioxybenzyl)-2,5(3H)- dioxo10,1 dihydro 5H pyrrolo[2,1 a]isoindole 1 carboxylic acid ethyl esterare obtained analogously to Example 39.

This application is a continuation-impart of application Serial No.848,914, filed October 27, 1959, now abandoned.

What we claim is:

1. An N-heterocyclic compound selected from the group consisting ofcompounds of the formulae N CO N O \CH/ wherein:

X represents a member selected from the group consisting of CO-O andCO-,

R represents a member selected from the group consisting of halogen,lower alkyl, cyclohexyl, phenyl, chlorophenyl, lower alkylphenyl, loweralkoxyphenyl, methylenedioxyphenyl, benzyl, chlorobenzyl, nitrobenzyl,lower alkylbenzyl, lower alkoxybenzyl and methylenedioxybenzyl, and

R represents a member selected from the group consisting of lowera'lkyl, lower chloroalkyl, allyl, cyclohexyl, phenyl, benzyl andbenzyloxy-lower alkyl.

2. A process for the production of an N-heterocyclic compound selectedfrom the group consisting of compounds of the formulae ,00 CO CH Xrepresents a member selected from the group consisting of -COO and CO--,

R represents a member selected from the group consisting of hydrogen,lower alkyl, cyclohexyl, phenyl, chlorophenyl, lower alkylphenyl, loweralkoxyphenyl, methylenedioxyphenyl, benzyl, chlorobenzyl, nitrobenzyl,lower alkylbenzyl, lower alkoxybenzyl and. methylenedioxybenzyl, and

R represents a member selected from the group consisting of lower alkyl,lower chloroalkyl, allyl, cyclohexyl, phenyl, benzyl and benzyloxy-loweralkyl,

which comprises heating the corresponding one of the compounds of theformulae R represents a member selected from the group consisting of'lower alkyl, lower chloroalkyl, allyl,, cyclohexyl, phenyl, benzyl andbenzyloxy-lower alkyl,

in a pyridine base to a temperature between about and boilingtemperature of the pyridine base until a substantially equimolecu'larportion of carbon dioxide is split off.

3. Process according to claim 2 wherein the starting material is boiledin pyridine until a substantially equimolecular portion of carbondioxide is split oil.

4. 3 (p chlorophenyl 2,5(3H) dioxo 5H pyrrolo[2,l-a]isoindole-l-carboxylic acid a'llyl ester.

5. 1 acetyl 3 methyl 5H pyrrolo[2, 1 a]iso indole-2,5 3H)-dione.

6. l acetyl 3 phenyl 5H pyrrolo[2,1 a]iso indole-2,5 (3H) -dione.

7. 1 cyano 3 phenyl 5H pyrrolo[2,1 a]iso indole-2,5 3H)-dione.

1. AN N-HETEROCYCLIC COMPOUND SELECTED FROM THE GROUP CONSISTING OFCOMPOUNDS OF THE FORMULAE